Cognitive function varies greatly throughout the day and night due to an intrinsic molecular clock localized hippocampal cells. In our last project period, we demonstrated that day-night differences in neuronal excitability, long-term potentiation, and memory are regulated by the circadian clock-controlled mechanisms such as kinase activation and ion channel regulation, and that excitability of central clock neurons in the suprachiasmatic nucleus is dysregulated in a mouse model of Alzheimer's disease. However, little is known about the underlying regulation of neuronal excitability by the molecular clock in hippocampus during both physiological and pathological states. Further investigation of the circadian regulation of passive and active membrane properties in excitatory pyramidal cells as well as inhibitory, parvalbumin-expressing interneurons is required to discover novel chronotherapeutic strategies for early intervention of hyper-excitability, cognitive dysfunction, and pathogenesis in Alzheimer's disease. In this competitive renewal request, we will test the novel hypotheses that the cell-autonomous molecular clock drives day-night differences in active and passive membrane properties of pyramidal neurons and PV+ interneurons at opposite times of the day. We predict that these anti-phase relationships promote day-night differences in excitatory-inhibitory balance, synaptic plasticity, and memory, and that disruption of circadian regulation of hippocampal membrane properties could contribute to hyper-excitability of the network and hasten cognitive impairment and pathogenesis. Using conditional transgenic mice, slice electrophysiology, bioluminescence imaging, chemogenetics, and behavioral assays, we will test whether rhythmic transcription and excitability of CA1 pyramidal neurons (Aim 1) and parvalbumin-expressing interneurons (Aim 2) are driven by the molecular clock and necessary for day-night differences in memory and plasticity. Aim 3 will use chemogenetics to determine whether restoration of day- night differences in the depolarization state and intrinsic excitability of CA1 pyramidal neurons is protective against Alzheimer's disease pathology and memory impairment. Altogether, these experiments have the potential to reveal an entirely novel mechanism by which the hippocampal clock regulates day-night differences in plasticity and cognition and could give critical insight into Alzheimer's disease hyperexcitability, memory impairment, and pathogenesis.